The Prospective Course of Rapid-Cycling Bipolar Disorder: Findings From the STEP-BD

Figure 1 presents an overview of the study. The study group consisted of the first 2,000 patients enrolled in STEP-BD and assessed between November 1999 and April 2002. Patients diagnosed with bipolar disorder not otherwise specified, schizoaffective disorder, cyclothymia, or unspecified condition were excluded from our analysis, as were patients with incomplete data. Of the 1,742 patients included, 75% were diagnosed with bipolar I disorder and 25% were diagnosed with bipolar II disorder. A total of 551 patients (32% of the original 1,742) did not complete 1 year of treatment and were designated as dropped. During the 1 year of prospective follow-up, only 58 (5%) of the remaining 1,191 patients had four or more mood disorder episodes (DSM-IV rapid cycling) ( Figure 1 ).

The mean age of the patients in the study was 40.4 years (SD=12.9). Other demographic characteristics are presented in Table 1 . The majority of the study group were Caucasian, female, and college educated. Table 2 presents clinical features of the participants at study entry. Patients entered the STEP-BD in a variety of symptomatic states, with approximately one-half of the group classified as either recovering or recovered. A total of 562 of the original 1,742 patients (32%) reported rapid cycling in the 12 months before study entry. The proportion of patients who reported rapid cycling in the prestudy year was higher for patients with bipolar II disorder than for those with bipolar I disorder ( Table 2 ).

The present study examined the course of cycling in a large group of bipolar patients (N=1,742) over the course of 1 year of treatment. Although we found the occurrence of four or more episodes in the follow-up year to be rare (only 5% of patients), recurrences at lower but still clinically relevant rates continued: 61% of the participants experienced between one and three episodes over the 12 months of follow-up.

The observed rate of DSM-IV-defined rapid cycling was much lower in the follow-up year (5% of patients) than in the year before entry into STEP-BD (32%). This difference is similar to the findings of Coryell et al. (15, 16), who observed that the percentage of rapid-cycling patients decreased from approximately 19% in the first year of treatment to 5% over the next 2–5 years. In the second study by Coryell et al. (16), in which patients were followed for approximately 15 years, four of five cases of rapid cycling ended within 2 years of their onset. Collectively, these results support the notion that rapid cycling is a transitory phenomenon in the course of bipolar illness.

The low prevalence of rapid cycling in our prospective study may have been attributable to several other factors. First, rapid cycling determined at study entry was diagnosed retrospectively, while the prospective observation used strict DSM-IV mood criteria and a minimum duration of 8 consecutive weeks of euthymia between episodes. Second, patients’ recollections of the number of cycles they experienced in the prior year may have been subject to retrospective bias in reporting (i.e., exaggeration of the number of episodes). Third, the use of a week-to-week prospective assessment method, such as the LIFE (17), may have revealed episodes that were not captured by psychiatric visits given as clinically needed. Last, the “model practice procedures” treatment employed by STEP-BD psychiatrists specially trained in treating mood disorders may have had a positive impact on the outcome of patients with a history of rapid cycling.

Nevertheless, our findings demonstrate that a reported history of recent rapid cycling is prognostically significant. Compared to patients without rapid cycling in the year before the study, patients who reported rapid cycling in the prior year were far less likely to be stable during the course of the follow-up year (41% versus 19%, respectively) and were more likely to have prospectively observed cycling, regardless of cycling frequency. Whereas patients with prior rapid cycling and patients without prior rapid cycling were equally likely to have one episode in the follow-up year (34% for each group), prior rapid cyclers were more likely to experience two or three episodes (38% versus 22%) and three times as likely to experience rapid cycling during follow-up (9% versus 3%). In our multivariate regression analysis, a history of rapid cycling emerged as the strongest predictor of cycling in the prospective year, regardless of cycling frequency.

The predictive validity of recent cycling is consistent with results reported by Bauer et al. (3), whose rapid-cycling patients had significantly more episodes than non-rapid-cycling patients during 12 or more months of prospective follow-up. From a clinical standpoint, we would not anticipate differences in the management of patients experiencing two or three episodes in a year and those with rapid cycling. Our data suggest that patients who report a recent history of rapid cycling are more vulnerable to cycling in the immediate future and that caution should be exercised in prescribing any medication with potential cycle-promoting activity.

Severity of illness at study entry proved to be a significant predictor of cycling outcome. Patients entering the study more depressed, more manic, or with poorer functioning were more likely to cycle in the follow-up year. The differences observed between the scores of stable patients and those with cycling episodes were clinically meaningful: entry MADRS scores for patients who had any prospectively observed episodes were in the moderately depressed range, whereas those who remained stable for the prospective year had scores indicating euthymia. On the Young Mania Rating Scale, clinically significant elevations in scores portended later rapid cycling, i.e., entry scores indicating mild hypomania were found in patients who later became rapid cyclers. Finally, the GAF scores revealed a clinically meaningful 8–13-point separation between patients who remained stable and those who went on to have cycling. The pattern of findings suggests that illness severity, particularly in regard to depressive symptoms and level of functioning, is an important clinical indicator in predicting which patients are more vulnerable to episode recurrence.

Patients who had stable, nonepisodic courses began their illness at approximately age 20, whereas patients who proved less stable over the course of the year, regardless of cycle frequency, began their illness approximately 3 years earlier, in their midteens. There have now been several studies (16, 18, 19) in which this relationship has been borne out, and it suggests that early onset of the disease elicits developmental vulnerability to cycling. However, age at illness onset did not prove to be a significant predictor of rapid cycling when more proximal predictors—such as baseline illness severity and recent history of rapid cycling—were taken into account.

A central question in the treatment of bipolar disorder, and more specifically rapid cycling, is whether or not antidepressants are of benefit or if they destabilize the course of illness (20, 21) . In our study, antidepressant exposure was associated with worse cycling, after we statistically controlled for the severity of baseline depression. In each outcome group, the likelihood of cycling increased linearly with antidepressant use during the first year, such that patients with antidepressant use were more than three times as likely to be rapid cyclers as were patients without such use.

We recognize that our results concerning antidepressant use must be viewed cautiously. First and foremost, patients who received antidepressants were not randomized to treatment. Because of the naturalistic design of the study, we were unable to control for numerous treatment factors, such as antidepressant dose, total time of antidepressant exposure, types of antidepressants used, and the presence of concomitant medications. Thus, we cannot conclude that antidepressants bore a direct causal relationship to increased cycling. Furthermore, antidepressants may have improved the course of bipolar disorder in ways different from those examined here, such as enhancing functioning or quality of life.

Our results can be contrasted with two previous studies by Coryell et al. (15, 16), both of which indicated that episodes of depression precede rapid cycling, independent of exposure to antidepressants. The authors of these studies concluded that the relationship between antidepressants and phase shifting was associative but not causative. In the present study, we found a relationship between antidepressant use and cycling even after controlling for the baseline level of depression. However, our design did not allow us to control for the level of depression at the time the antidepressants were given.

We failed to find any naturally occurring cutoff point to distinguish patients with four or more episodes from those with two or three episodes per year. Box plots of MADRS, Young Mania Rating Scale, and GAF scores and age at onset of illness revealed a nearly linear relationship between these clinical measures and the number of episodes in the follow-up year. Similar to the cycling pattern in the examination by Kupka et al. (4), rapid cycling in our study existed along a continuum and suggests that a dimensional, rather than categorical, approach may better conceptualize the phenomenon of frequent cycling.

While a prior history of cycle frequency may have influenced the number of psychiatric visits during the prospective period, both the depression score at study entry and the number of visits independently predicted cycle frequency at follow-up. Thus, patients with more serious illnesses were likely to be seen by psychiatrists more frequently, but the association between illness severity and cycle frequency could not be accounted for by this confound. Nonetheless, researchers examining the phenomenon of rapid cycling should take frequency of observation into account when interpreting results, particularly in naturalistic studies.

Several limitations of our study deserve further comment. The STEP-BD was based at academic, specialty, and tertiary-care sites across the United States, which may have attracted a more select population than might be found in the general community. The population of the STEP-BD was of limited diversity in both race and socioeconomic status, which limits the generalizability of our findings to more diverse populations. Many patients were on complex and changing polypharmacy regimens, and thus the number of medication variables was too great to allow a more in-depth analysis of individual pharmacological treatments and their potential benefits or liabilities. Finally, observation intervals greater than 1 year may be needed to assess whether rapid cycling represents a lifelong vulnerability with poorer prognosis or simply a course modifier that requires longer than 1 year to resolve.

Future studies specifically examining age at onset and its relationship to long-term outcome may be most warranted, as delaying or avoiding the introduction of antidepressants at a young age may enhance the long-term outcome of this treatment-refractory variant. Newer agents, such as quetiapine and lamotrigine, may be increasingly useful, as recent studies have demonstrated their efficacy in treating the depressed phase of both rapid-cycling patients and those with nonrapid cycling (22, 23) .

Received Aug. 24, 2005; revisions received April 13 and Aug. 6, 2007; accepted Aug. 18, 2007 (doi: 10.1176/appi.ajp.2007.05081484). From the Department of Psychiatry, University of Colorado Health Sciences Center. Address correspondence and reprint requests to Dr. Schneck, Department of Psychiatry, University of Colorado Health Sciences Center, Box A011-15, 4455 East 12th Ave., Denver, CO 80220; [email protected] (e-mail).

Dr. Wisniewski has served as a consultant to Case Western University, Cyberonics, ImaRx Therapeutics, Bristol-Myers Squibb, and Organon. Dr. Gyulai has provided CME lectures for Abbott Laboratories; and an NIMH-funded clinical trial in which he participates receives risperidone from Janssen. Dr. Allen has received research support from Abbott, Alexza, Bristol-Myers Squibb, and Pfizer; he has served on the speakers bureaus of AstraZeneca, Bristol-Myers Squibb, and Pfizer; and he has been a consultant for Abbott, Alexza, Bristol-Myers Squibb, and Pfizer. Dr. Thase has served as an advisor or consultant to AstraZeneca, Bristol-Myers Squibb, Cephalon, Cyberonics, Eli Lilly, GlaxoSmithKline, Janssen, MedAvante, Neuronetics, Novartis, Organon, Sepracor, Shire, Supernus, and Wyeth; he has also served on the speakers bureaus of AstraZeneca, Bristol-Myers Squibb, Cyberonics, Eli Lilly, GlaxoSmithKline, Organon, Sanofi-Aventis, and Wyeth; he has provided expert testimony for Jones Day (Wyeth litigation) and Phillips Lytle (GlaxoSmithKline litigation); he is a shareholder with MedAvante; he receives income from royalties and/or patents with American Psychiatric Publishing, Guilford Publications, and Herald House; and his wife is the senior medical director for Advogent. Dr. Sachs has received research support from Abbott, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Janssen, Memory Pharmaceuticals, NIMH, Novartis, Pfizer, Repligen, Shire, and Wyeth; he has served on the speakers bureaus of Abbott, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Janssen, Memory Pharmaceuticals, Novartis, Pfizer, Sanofi-Aventis, and Wyeth; he has served as an advisory board member or consultant for Abbott, AstraZeneca, Bristol-Myers Squibb, Cephalon, CNS Response, Elan Pharmaceuticals, Eli Lilly, GlaxoSmithKline, Janssen, Memory Pharmaceuticals, Merck, Novartis, Organon, Pfizer, Repligen, Sanofi-Aventis, Shire, Sigma-Tau, Solvay, and Wyeth; and his spouse is a shareholder with Concordant Rater Systems. Drs. Schneck, Miklowitz, and Miyahara and Ms. Araga report no competing interests.

Funded in whole or in part with federal funds under NIMH contract N01-MH-80001.

Any opinions, findings, and conclusions or recommendations expressed in this publication are those of the authors and do not necessarily reflect the views of NIMH. The Publication Committee of the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) approved this article.